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Ovarian cancer stem-like cells show induced translineage-differentiation capacity and are suppressed by alkaline phosphatase inhibitor.

Liu KC, Yo YT, Huang RL, Wang YC, Liao YP, Huang TS, Chao TK, Lin CK, Weng SJ, Ma KH, Chang CC, Yu MH, Lai HC - Oncotarget (2013)

Bottom Line: Alkaline phosphatase (ALP) was highly expressed in SR1 spheroids, decreased in SR2 spheroids, and was absent in differentiated progenies in accordance with the loss of stemness properties.We verified that ALP can be a marker for ovarian CSLCs, and patients with greater ALP expression is related to advanced clinical stages and have a higher risk of recurrence and lower survival rate.In summary, this research provides a plastic ovarian cancer stem cell model and a new understanding of the cross-link between stem cells and cancers.This results show that ovarian CSLCs can be suppressed by levamisole.

View Article: PubMed Central - PubMed

Affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.

ABSTRACT
Spheroid formation is one property of stem cells-such as embryo-derived or neural stem cells-that has been used for the enrichment of cancer stem-like cells (CSLCs). However, it is unclear whether CSLC-derived spheroids are heterogeneous or whether they share common embryonic stemness properties. Understanding these features might lead to novel therapeutic approaches. Ovarian carcinoma is a deadly disease of women. We identified two types of spheroids (SR1 and SR2) from ovarian cancer cell lines and patients' specimens according to their morphology. Both types expressed stemness markers and could self-renew and initiate tumors when a low number of cells were used. Only SR1 could differentiate into multiple-lineage cell types under specific induction conditions. SR1 spheroids could differentiate to SR2 spheroids through epithelial-mesenchymal transition. Alkaline phosphatase (ALP) was highly expressed in SR1 spheroids, decreased in SR2 spheroids, and was absent in differentiated progenies in accordance with the loss of stemness properties. We verified that ALP can be a marker for ovarian CSLCs, and patients with greater ALP expression is related to advanced clinical stages and have a higher risk of recurrence and lower survival rate. The ALP inhibitor, levamisole, disrupted the self-renewal of ovarian CSLCs in vitro and tumor growth in vivo. In summary, this research provides a plastic ovarian cancer stem cell model and a new understanding of the cross-link between stem cells and cancers.This results show that ovarian CSLCs can be suppressed by levamisole. Our findings demonstrated that some ovarian CSLCs may restore ALP activity, and this suggests that inhibition of ALP activity may present a new opportunity for treatment of ovarian cancer.

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Inhibition of ALP activity by levamisole interferes with the formation of spheroids and tumors in ovarian CSLCs(A) Levamisole inhibited spheroid formation of dissociated single CP70SR1 cells and specimen-derived SR1 cells. The inhibitory efficacy of levamisole differed between spheroids isolated from different patients. For in vivo analysis of the effect of levamisole on ovarian CSLCs, mice were implanted peritoneally with CP70 cells and then given oral levamisole (B) or placebo (C). Tumor volume was significantly decreased in levamisole-treated mice as analyzed using a micro-PET image system. (D) ALP expression was associated with serous type and a high grade of EOC. In addition, metastatic cancer with the greatest expression of ALP indicated that ALP was related with advanced stage of EOC. Kaplan–Meier analysis of the probability of recurrence (E) and overall survival rate (F) in ovarian cancer patients stratified according to ALP expression (n = 73).
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Figure 6: Inhibition of ALP activity by levamisole interferes with the formation of spheroids and tumors in ovarian CSLCs(A) Levamisole inhibited spheroid formation of dissociated single CP70SR1 cells and specimen-derived SR1 cells. The inhibitory efficacy of levamisole differed between spheroids isolated from different patients. For in vivo analysis of the effect of levamisole on ovarian CSLCs, mice were implanted peritoneally with CP70 cells and then given oral levamisole (B) or placebo (C). Tumor volume was significantly decreased in levamisole-treated mice as analyzed using a micro-PET image system. (D) ALP expression was associated with serous type and a high grade of EOC. In addition, metastatic cancer with the greatest expression of ALP indicated that ALP was related with advanced stage of EOC. Kaplan–Meier analysis of the probability of recurrence (E) and overall survival rate (F) in ovarian cancer patients stratified according to ALP expression (n = 73).

Mentions: The upregulation of ALP in hepatocellular CSLCs has been reported recently [25]. We aimed to clarify whether ALP plays an important role in ovarian CSLCs. Levamisole suppressed sphere formation of SR1 originating from the CP70 cell line and human specimens (Figure 6A). The quantity of spheres formed and basic morphology of these spheres were also significantly affected, indicating that ALP inactivation inhibited ovarian CSLC self-renewal (Supplementary Information, Figure S6C). Tumor formation was repressed only in mice that had received oral levamisole (Figure 6B and 6C).


Ovarian cancer stem-like cells show induced translineage-differentiation capacity and are suppressed by alkaline phosphatase inhibitor.

Liu KC, Yo YT, Huang RL, Wang YC, Liao YP, Huang TS, Chao TK, Lin CK, Weng SJ, Ma KH, Chang CC, Yu MH, Lai HC - Oncotarget (2013)

Inhibition of ALP activity by levamisole interferes with the formation of spheroids and tumors in ovarian CSLCs(A) Levamisole inhibited spheroid formation of dissociated single CP70SR1 cells and specimen-derived SR1 cells. The inhibitory efficacy of levamisole differed between spheroids isolated from different patients. For in vivo analysis of the effect of levamisole on ovarian CSLCs, mice were implanted peritoneally with CP70 cells and then given oral levamisole (B) or placebo (C). Tumor volume was significantly decreased in levamisole-treated mice as analyzed using a micro-PET image system. (D) ALP expression was associated with serous type and a high grade of EOC. In addition, metastatic cancer with the greatest expression of ALP indicated that ALP was related with advanced stage of EOC. Kaplan–Meier analysis of the probability of recurrence (E) and overall survival rate (F) in ovarian cancer patients stratified according to ALP expression (n = 73).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3926833&req=5

Figure 6: Inhibition of ALP activity by levamisole interferes with the formation of spheroids and tumors in ovarian CSLCs(A) Levamisole inhibited spheroid formation of dissociated single CP70SR1 cells and specimen-derived SR1 cells. The inhibitory efficacy of levamisole differed between spheroids isolated from different patients. For in vivo analysis of the effect of levamisole on ovarian CSLCs, mice were implanted peritoneally with CP70 cells and then given oral levamisole (B) or placebo (C). Tumor volume was significantly decreased in levamisole-treated mice as analyzed using a micro-PET image system. (D) ALP expression was associated with serous type and a high grade of EOC. In addition, metastatic cancer with the greatest expression of ALP indicated that ALP was related with advanced stage of EOC. Kaplan–Meier analysis of the probability of recurrence (E) and overall survival rate (F) in ovarian cancer patients stratified according to ALP expression (n = 73).
Mentions: The upregulation of ALP in hepatocellular CSLCs has been reported recently [25]. We aimed to clarify whether ALP plays an important role in ovarian CSLCs. Levamisole suppressed sphere formation of SR1 originating from the CP70 cell line and human specimens (Figure 6A). The quantity of spheres formed and basic morphology of these spheres were also significantly affected, indicating that ALP inactivation inhibited ovarian CSLC self-renewal (Supplementary Information, Figure S6C). Tumor formation was repressed only in mice that had received oral levamisole (Figure 6B and 6C).

Bottom Line: Alkaline phosphatase (ALP) was highly expressed in SR1 spheroids, decreased in SR2 spheroids, and was absent in differentiated progenies in accordance with the loss of stemness properties.We verified that ALP can be a marker for ovarian CSLCs, and patients with greater ALP expression is related to advanced clinical stages and have a higher risk of recurrence and lower survival rate.In summary, this research provides a plastic ovarian cancer stem cell model and a new understanding of the cross-link between stem cells and cancers.This results show that ovarian CSLCs can be suppressed by levamisole.

View Article: PubMed Central - PubMed

Affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.

ABSTRACT
Spheroid formation is one property of stem cells-such as embryo-derived or neural stem cells-that has been used for the enrichment of cancer stem-like cells (CSLCs). However, it is unclear whether CSLC-derived spheroids are heterogeneous or whether they share common embryonic stemness properties. Understanding these features might lead to novel therapeutic approaches. Ovarian carcinoma is a deadly disease of women. We identified two types of spheroids (SR1 and SR2) from ovarian cancer cell lines and patients' specimens according to their morphology. Both types expressed stemness markers and could self-renew and initiate tumors when a low number of cells were used. Only SR1 could differentiate into multiple-lineage cell types under specific induction conditions. SR1 spheroids could differentiate to SR2 spheroids through epithelial-mesenchymal transition. Alkaline phosphatase (ALP) was highly expressed in SR1 spheroids, decreased in SR2 spheroids, and was absent in differentiated progenies in accordance with the loss of stemness properties. We verified that ALP can be a marker for ovarian CSLCs, and patients with greater ALP expression is related to advanced clinical stages and have a higher risk of recurrence and lower survival rate. The ALP inhibitor, levamisole, disrupted the self-renewal of ovarian CSLCs in vitro and tumor growth in vivo. In summary, this research provides a plastic ovarian cancer stem cell model and a new understanding of the cross-link between stem cells and cancers.This results show that ovarian CSLCs can be suppressed by levamisole. Our findings demonstrated that some ovarian CSLCs may restore ALP activity, and this suggests that inhibition of ALP activity may present a new opportunity for treatment of ovarian cancer.

Show MeSH
Related in: MedlinePlus